Molecular switches based on cis/trans isomerization of bf2-coordinated azo compounds

ABSTRACT

Provided herein are photochromic organic compounds of Formula I or Formula II, which are useful as molecular switches capable of being triggered via a cis/trans isomerization process. Methods of using the molecular switch compounds to form photopharmaceutical compounds that may be used to provide selective spatiotemporal activation of pharmaceutical agents are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage application under 35 U.S.C.§371 of PCT/US14/52983, filed Aug. 27, 2014, which claims the benefit ofpriority from U.S. Provisional Patent Application No. 61/870,572, filedAug. 27, 2013. Each of these applications is hereby incorporated byreference in its entirety.

BACKGROUND

Photoreversible, organic compounds are especially attractive materialsfor use as molecular switches. Photoreversible compounds are stimulatedby light, i.e., they provide reversible switching processes based onphotochemically induced interconversions. Photochromism, a reversiblechange induced by light irradiation between two states of a moleculehaving different electromagnetic absorption spectra, is commonlyassociated with such photoreversible systems. Photochromic switchingprocesses are typically based on photocyclization of isomers, theconversion of olefinic (cis/trans) isomers, photoinduced electrontransfer, and keto-enol tautomerism.

Photochromic molecular switches based on the trans→cis isomerization ofazobenzene are useful for many purposes, including industrial dyes,actuators, nonlinear optical devices, liquid crystals, molecularmachines, ion channel modulators, and the like. Ultraviolet (UV) lightoften is used to induce the trans→cis isomerization. However, UV lightcan be harmful in certain applications, especially those involving invivo systems. Hence, there is a significant need in the art forphotochromic molecular switches that can be toggled between cis andtrans states using lower energy electromagnetic irradiation with lessscattering and that can penetrate tissues more easily (i.e., red and NIRlight).

SUMMARY OF THE INVENTION

Provided herein are compounds, photochromic materials comprising suchcompounds, and methods of using such compounds as molecular switches. Inan embodiment, the compounds may be used in photopharmaceuticalcompounds as molecular switches that allow for selective spatiotemporalactivation of pharmaceutical agents.

Accordingly, in one aspect, provided herein is a compound of Formula II:

or a salt thereof, wherein

N═N—R² can be oriented cis or trans to the tricycle;

R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl, OH,O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,or NHC(O)(C₁₋₆-alkyl);

R² is C₆₋₁₉-aryl or C₃₋₁₄-heteroaryl, wherein the C₆₋₁₉-aryl orC₃₋₁₄-heteroaryl is independently substituted one or more times at thepara and/or ortho position with C₁₋₆-alkyl, C₆₋₁₉-aryl,C₃₋₁₄-heteroalkyl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl); and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently, H, C₁₋₆-alkyl,C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, NHC(O)(C₁₋₆-alkyl) or a group corresponding to a smallmolecule pharmaceutical; or

R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together,form a fused aryl, fused heteroaryl, fused C₃₋₆-cycloalkyl, or fusedheterocycle, wherein the fused aryl, fused heteroaryl, fused cycloalkyl,or fused heterocycle can be optionally substituted one or more timeswith C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).

In another aspect, provided herein is a compound of the Formula I:

or a salt thereof, wherein

N═N—R² can be oriented cis or trans to the tricycle;

R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl, OH,O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,or NHC(O)(C₁₋₆-alkyl);

R² is unsubstituted C₆₋₁₉-aryl or unsubstituted C₃₋₁₄-heteroaryl; and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently, H, C₁₋₆-alkyl,C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, NHC(O)(C₁₋₆-alkyl) or a group corresponding to a smallmolecule pharmaceutical; or

R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together,form a fused aryl, fused heteroaryl, fused C₃₋₆-cycloalkyl, or fusedheterocycle, wherein the fused aryl, fused heteroaryl, fused cycloalkyl,or fused heterocycle can be optionally substituted one or more timeswith C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).

In certain embodiments of Formula I and Formula II, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are each, independently, H.

In certain other embodiments of Formula I and Formula II, R¹ is CN.

In certain embodiments of Formula I, R² is unsubstituted phenyl.

In certain embodiments of Formula II, R² is phenyl, wherein the phenylis substituted at the para position. In certain other embodiments ofFormula II, R² is phenyl, wherein the phenyl is substituted at the paraposition with N(CH₃)₂, OCH₃, piperazinyl, (N-methyl)piperazinyl,piperidinyl, morpholinyl or a group corresponding to a cholesterolmolecule.

In some embodiments of Formula I and Formula II, N═N—R² is oriented cisto the tricycle. In other embodiments of Formula I and Formula II,N═N—R² is oriented trans to the tricycle.

In certain embodiments of Formula I and Formula II, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are each, independently, a bond to a pharmaceutical agent.

In one aspect, provided herein is a photochromic molecular switchcomprising at least one compound of Formula I or a salt thereof. Inanother aspect, provided herein is a photochromic molecular switchcomprising at least one compound of Formula II or a salt thereof.

In yet another aspect, provided herein is a method of switching amolecular switch, wherein the molecular switch comprises a compound ofFormula I or a salt thereof; wherein the method comprises applyingelectromagnetic radiation to the molecular switch at a first wavelengtheffective to cause the trans→cis isomerization of the compound ofFormula I or salt thereof; or applying electromagnetic radiation to themolecular switch at a second wavelength effective to cause the cis→transisomerization of the compound of Formula I or salt thereof; or acombination thereof.

In still another aspect, provided herein is a method of switching amolecular switch, wherein the molecular switch comprises a compound ofFormula II or a salt thereof; wherein the method comprises applyingelectromagnetic radiation to the molecular switch at a first wavelengtheffective to cause the trans→cis isomerization of the compound ofFormula II or salt thereof; or applying electromagnetic radiation to themolecular switch at a second wavelength effective to cause the cis→transisomerization of the compound of Formula II or salt thereof; or acombination thereof.

In certain embodiments, the molecular switch comprising the salt ofFormula I or the salt of Formula II is reacted with a pharmaceuticallyacceptable salt to form a photopharmaceutical compound. In certainembodiments, the pharmaceutically acceptable salt is a salt of a smallmolecule pharmaceutical.

In one embodiment, the molecular switch comprising the compound ofFormula I or the compound of Formula II or a photopharmaceuticalcompound thereof is stable in water or biological fluid. In anotherembodiment, the molecular switch comprising the compound of Formula I orthe compound of Formula II or a photopharmaceutical compound thereofdoes not substantially hydrolyze in water or biological fluid.

In certain embodiments, a method of treating a patient in need oftherapy comprises administering a therapeutically effective amount of aphotopharmaceutical compound to a patient in need thereof; and applyingelectromagnetic radiation to a tissue comprising the photopharmaceuticalcompound at a first wavelength effective to cause the trans→cisisomerization or applying electromagnetic radiation to thephotopharmaceutical compound at a second wavelength effective to causethe cis→trans isomerization or a combination thereof.

In one embodiment of the methods of switching the molecular switch, theelectromagnetic radiation is generated by an infrared light sourceand/or a visible light source.

In another embodiment of the methods of switching the molecular switch,the electromagnetic radiation is generated by a visible light source.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1a schematically illustrates a photopharmaceutical compoundcomprising a pharmaceutical agent (circle, star, triangle, square) boundto Compound 1, where activation of the pharmaceutical agent is triggeredby isomerization of Compound 1.

FIG. 1b shows the UV/vis spectral changes upon the photoisomerization ofCompound 1 in deoxygenated CH₂Cl₂ (0.1 mM). The black trace is ofCompound 1 equilibrated in the dark (mainly trans), which uponirradiation at λ₁=570 nm gives the cis photostationary state (PSS, bluetrace), which when irradiated at λ₂=450 nm gives the trans PSS (redtrace).

FIG. 1c shows multiple isomerization cycles of Compound 1 (0.1 mM) inCH₂Cl₂ (not deoxygenated) after alternative irradiation at λ₁=570 nm(red trace) and λ₂=450 nm (black trace).

FIG. 2 shows the visible light-induced trans/cis isomerization ofCompound 1.

FIG. 3 shows the calculated (B3LYP/6-311++G**) molecular orbital energylevels, transition energies and oscillator strengths of the n→π* andπ_(nb)→π* transitions of the trans isomer of Compound 1.

FIG. 4 shows the optimized structure of Compound 1-trans.

FIG. 5 shows the optimized structure of Compound 1-cis.

FIG. 6 shows the HOMO of Compound 1-trans (0.05 isosurface).

FIG. 7 shows the HOMO-2 of Compound 1-trans (0.05 isosurface).

FIG. 8 shows the calculated UV/Vis spectrum of Compound 1-trans.

FIG. 9 shows the calculated UV/Vis spectrum of Compound 1-cis.

FIG. 10 shows the calculated UV/Vis spectrum of Na-Azo complex (trans).

FIG. 11 shows the calculated UV/Vis spectrum of Na-Azo complex (cis).

FIG. 12 shows the calculated substituent effects (X) on HOMO-LUMOenergies of BF₂-Azo compounds. Substitution of H by the π-acceptorsubstituent CN decreases the HOMO-LUMO energy gap by stabilizing theHOMO more than the LUMO. Substitution of H by a π-donor OH substituentinductively stabilizes both HOMO and LUMO, but the π-donor componentstrongly destabilizes the HOMO, resulting in a lower overall HOMO-LUMOenergy gap.

FIG. 13 shows the calculated substituent effects (X) on UV/Vis spectraof BF₂-Azo complexes (trans).

FIG. 14 depicts the idealized MO picture for the π-orbitals of theN—C—C—N—N skeleton of the azo compounds. Energies increase with thenumber of nodes. The HOMO→LUMO transition is from a MO that isπ-nonbonding to one which is π*-antibonding between either the NN or CNsubunits, as shown.

FIG. 15 demonstrates the H-Azo trans vs. cis MO levels: strippedmolecules. The π-MOs follow the same nodal pattern as those in FIG. 14.Lone pair MOs rise in energy from trans→cis due to greaterelectron-electron repulsion in cis configuration.

FIG. 16 demonstrates the H-Azo vs. BF₂-Azo MO levels: strippedmolecules. BF₂ coordination lowers all energy levels by electronwithdrawal; lone pair levels are lowered even more significantly bycoordination and become bonding instead of non-bonding. The HOMO→LUMOtransition is from an MO that is π-nonbonding to one which isπ*-antibonding between either the NN or CN subunits. Unlike the H—compound, only the NN linkage is subject to trans→cis isomerization(switching) in the BF₂ compound; the rest of the system is clamped inposition by coordination to the BF₂ group.

FIG. 17 shows the calculated BF₂-Azo trans vs. cis MO levels: strippedmolecules. Higher energy HOMO→LUMO transitions in the cis isomer resultfrom the stabilization of the HOMO in the latter, without significantstabilization of the corresponding LUMO.

FIG. 18 depicts the BF₂-Azo trans vs. cis HOMO→LUMO levels: fullmolecules. Higher energy HOMO→LUMO transitions in the cis isomer resultfrom the stabilization of the HOMO in the latter, without significantstabilization of the corresponding LUMO.

FIG. 19 (a) The UV/Vis spectral changes upon the photoisomerization of 2in CH₂Cl₂ (0.2 mM). The black trace is of 2 equilibrated under dark(mainly trans), which upon irradiation at λ=630 nm gives the cis PSS(blue trace). Irradiating the latter at λ=490 nm gives the trans PSS(red trace). (b) The UV/Vis spectral changes upon the photoisomerizationof 3 in CH₂Cl₂ (0.1 mM). The black trace is of 3 equilibrated underdark, which upon irradiation at λ=640 nm gives the cis PSS (blue trace).Irradiating the latter at λ=490 nm gives the trans PSS (red trace).

FIG. 20. (a) NIR light-induced trans/cis isomerization of 4. (b) TheUV/Vis spectral changes upon the photoisomerization of 4 in CH₂Cl₂ (0.2mM). The black trace is of 4 equilibrated under dark (mainly trans),which upon irradiation at λ=710 nm gives the cis populated state (redtrace).

FIG. 21. UV/Vis spectral changes upon photoisomerization of (a) 5, (b) 6and (c) 7. The black trace is equilibrated complex in the dark (mainlytrans), which upon irradiation at λ=710 nm gives the cis populated state(red trace); (d) Overlay of the π-π* absorption bands of the transisomers of 5-7, represented by black, blue and red lines, respectively.

FIG. 22. (a) Switching cycles of 4 in acetonitrile:PBS buffer (1:1)monitored by following the absorbance at λ=681 nm (black trace) uponirradiation at λ=710 nm then leaving in the dark. (b) UV/Vis spectrafollowing an acetonitrile:PBS buffer (1:1) solution of the azo-BF₂complex 4 at 25° C. The interval between each scan is 20 min.

FIG. 23. ORTEP drawing (50% probability ellipsoids) of the crystalstructures of (a) 2 and (b) 4. The hydrogen atoms were removed forclarity.

FIG. 24. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 2 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 25. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 2-trans(contains a small percentage of the cis isomer) in CD₂Cl₂ at 294 K.

FIG. 26. ¹H NMR spectrum of 2 after being stored in the dark. Theequilibrated mixture of 2 was determined to have an isomer ratio of 93:7(trans:cis).

FIG. 27. ¹H NMR spectra of the PSS of 2 at a) 490 nm and b) 630 nm inCD₂Cl₂ at 294 K. The PSS isomer ratios of 92±1% trans at λ_(irr)=490 nm,and 96±1% cis at λ_(irr)=630 nm are the averages of three experiments.

FIG. 28. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 3 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 29. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 3-cis (containsa small percentage of the trans isomer) in CD₂Cl₂ at 294 K.

FIG. 30. ¹H NMR spectrum of 3 after being stored in the dark. Theequilibrated mixture of 3 was determined to have an isomer ratio of58:42 (trans:cis).

FIG. 31. ¹H NMR spectra of the PSS of 3 at a) 490 nm and b) 640 nm inCD₂Cl₂ at 294 K. The PSS isomer ratios of 56±1% trans at λ_(irr)=490 nm,and 79±1% cis at λ_(irr)=640 nm are the averages of three experiments.

FIG. 32. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 4 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 33. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 4-trans inCD₂Cl₂ at 294 K.

FIG. 34. ¹H NMR spectrum of 4 after being stored in the dark. Theequilibrated mixture of 4 was determined to have an isomer ratio of 97:3(trans:cis).

FIG. 35. ¹H NMR spectrum recording the lowest estimation of PSS of 4 at710 nm in CD₂Cl₂ at 294 K. The PSS isomer ratio of 63±1% cis atλ_(irr)=710 nm is the average of three experiments.

FIG. 36. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 5 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 37. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 5-trans(contains a small percentage of the cis isomer) in CD₂Cl₂ at 294 K.

FIG. 38. ¹H NMR spectrum of 5 after being stored in the dark. Theequilibrated mixture of 5 was determined to have an isomer ratio of 98:2(trans:cis).

FIG. 39. ¹H NMR spectrum recording the lowest estimation of PSS of 5 at710 nm in CD₂Cl₂ at 294 K. The PSS isomer ratio of 28±1% cis atλ_(irr)=710 nm is the average of three experiments.

FIG. 40. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 7 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 41. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 7-trans(contains a small percentage of the cis isomer) in CD₂Cl₂ at 294 K.

FIG. 42. ¹H NMR spectrum of 7 after being stored in the dark. Theequilibrated mixture of 7 was determined to have an isomer ratio of 94:6(trans:cis).

FIG. 43. ¹H NMR spectrum recording the lowest estimation of PSS of 7 at710 nm in CD₂Cl₂ at 294 K. The PSS isomer ratio of 82±1% cis atλ_(irr)=710 nm is the average of three experiments.

FIG. 44. a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 6 (contains asmall percentage of the Z isomer) in CDCl₃ at 294 K.

FIG. 45. a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 6-trans(contains a small percentage of the cis isomer) in CD₂Cl₂ at 294 K.

FIG. 46. ¹H NMR spectrum of 6 after being stored in the dark. Theequilibrated mixture of 7 was determined to have an isomer ratio of 97:3(trans:cis).

FIG. 47. ¹H NMR spectrum recording the lowest estimation of PSS of 6 at710 nm in CD₂Cl₂ at 294 K. The PSS isomer ratio of 49±1% cis atλ_(irr)=710 nm is the average of three experiments.

FIG. 48. Plots of Absorbance versus time showing the first-order decaysof (a) 2 and (b) 3 in degassed CH₂Cl₂ at 294 K starting from PSS630 andPSS640, respectively. The black lines represent the experimental resultswhile the red lines represent the theoretical first-order fits.

FIG. 49. Plots of cis isomer ratio (%) versus time showing thefirst-order decay of 4 in CD₂Cl₂ at 294 K starting from its PSS710. Theblack dots represent the experimental results while the red linerepresents the theoretical first-order fit.

FIG. 50. ¹H NMR spectra of a) 4 in CD₃CN, b) 4 with water in CD₃CN andc) Hydrazone 4 in CD₃CN at 294 K.

FIG. 51. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of4 incubated with 10 mM GSH at 25° C. The interval between each scan is˜20 min. A half-life of 2.5 h is observed.

FIG. 52. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of5 at 25° C. The interval between each scan is ˜20 min. A half-life of 2h is observed.

FIG. 53. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of5 incubated with 10 mM GSH at 25° C. The interval between each scan is˜20 min. A half-life of 2.1 h is observed.

FIG. 54. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of6 at 25° C. The interval between each scan is ˜20 min. A half-life of1.2 h was observed.

FIG. 55. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of6 incubated with 10 mM GSH at 25° C. The interval between each scan is˜10 min. A half-life of 1.3 h was observed.

FIG. 56. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of7 at 25° C. The interval between each scan is ˜20 min. A half-life of0.9 h was observed.

FIG. 57. UV-Vis spectra following an acetonitrile:PBS (1:1) solution of7 incubated with 10 mM GSH at 25° C. The interval between each scan is˜25 min. A half-life of 1.0 h was observed.

DETAILED DESCRIPTION OF THE INVENTION Photochromic Compounds of theInvention

Provided herein are compounds for use as photochromic molecularswitches. In an embodiment, the compounds may be used inphotopharmaceutical compounds as molecular switches that allow forselective spatiotemporal activation of pharmaceutical agents. Asillustrated in FIG. 1a , one or more pharmaceutical agents (genericallydepicted as circles, stars, triangles and squares) may be bound toCompound 1 and activated by isomerization of Compound 1. Activation isschematically illustrated in FIG. 1a as a change from a filled shape(e.g., circle, star, triangle, square) to an unfilled shape or viceversa. Activation may, for example, include formation or breaking of oneor more chemical bonds, severing of the molecular switch andpharmaceutical agent moieties, a change in configuration of the moleculeto increase or decrease steric and/or electronic interactions (e.g.,between the pharmaceutical agent and a protein binding pocket), atransfer of charge to/from/within the pharmaceutical agent, photonabsorption or emission by the pharmaceutical agent, and/or any otherprocess that changes the pharmaceutical agent from a first state to asecond state, wherein the pharmaceutical agent in the first state doesnot alter a biological material or process, and wherein thepharmaceutical agent in the second state alters a biological material orprocess.

Also provided herein are methods of switching a molecular switch whereinelectromagnetic radiation is applied to the molecular switch at a firstwavelength effective to cause the trans→cis isomerization of a compoundof Formula I or Formula II, a salt of Formula I or Formula II, or aphotopharmaceutical compound derived from Formula I or Formula II; orapplying electromagnetic radiation to the molecular switch at a secondwavelength effective to cause the cis→trans isomerization of a compoundof Formula I or Formula II, a salt of Formula I or Formula II, or aphotopharmaceutical compound derived from Formula I or Formula II; or acombination thereof.

In one aspect, provided herein are compounds of Formula II:

or a salt thereof, wherein

N═N—R² can be oriented cis or trans to the tricycle;

R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl, OH,O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,or NHC(O)(C₁₋₆-alkyl);

R² is C₆₋₁₉-aryl or C₃₋₁₄-heteroaryl, wherein the C₆₋₁₉-aryl orC₃₋₁₄-heteroaryl is independently substituted one or more times at thepara and/or ortho position with C₁₋₆-alkyl, C₆₋₁₉-aryl,C₃₋₁₄-heteroalkyl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl); and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently, H, C₁₋₆-alkyl,C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, NHC(O)(C₁₋₆-alkyl) or a group corresponding to a smallmolecule pharmaceutical; or

R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together,form a fused aryl, fused heteroaryl, fused C₃₋₆-cycloalkyl, or fusedheterocycle, wherein the fused aryl, fused heteroaryl, fused cycloalkyl,or fused heterocycle can be optionally substituted one or more timeswith C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).

In another aspect, provided herein is a compound of the Formula I:

or a salt thereof, wherein

N═N—R² can be oriented cis or trans to the tricycle;

R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl, OH,O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,or NHC(O)(C₁₋₆-alkyl);

R² is unsubstituted C₆₋₁₉-aryl or unsubstituted C₃₋₁₄-heteroaryl; and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently, H, C₁₋₆-alkyl,C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, NHC(O)(C₁₋₆-alkyl) or a group corresponding to a smallmolecule pharmaceutical; or

R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together,form a fused aryl, fused heteroaryl, fused C₃₋₆-cycloalkyl, or fusedheterocycle, wherein the fused aryl, fused heteroaryl, fused cycloalkyl,or fused heterocycle can be optionally substituted one or more timeswith C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).

In certain embodiments of Formula I and Formula II, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are each, independently, H.

In certain other embodiments of Formula I and Formula II, R¹ is CN.

In certain embodiments of Formula I, R² is unsubstituted phenyl.

In certain embodiments of Formula II, R² is phenyl, wherein the phenylis substituted at the para position. In certain other embodiments ofFormula II, R² is phenyl, wherein the phenyl is substituted at the paraposition with N(CH₃)₂, OCH₃, piperazinyl, (N-methyl)piperazinyl,piperidinyl, morpholinyl or a group corresponding to a cholesterolmolecule.

In some embodiments of Formula I and Formula II, N═N—R² is oriented cisto the tricycle. In other embodiments of Formula I and Formula II,N═N—R² is oriented trans to the tricycle.

In some embodiments of Formula II, the phenyl is substituted at the paraposition with OMe.

In other embodiments of Formula II, the phenyl is substituted at thepara position with N(CH₃)₂.

In other embodiments of Formula II, the phenyl is substituted at thepara position with piperazinyl.

In other embodiments of Formula II, the phenyl is substituted at thepara position with piperidinyl.

In other embodiments of Formula II, the phenyl is substituted at thepara position with (N-methyl)piperazinyl.

In other embodiments of Formula II, the phenyl is substituted at thepara position with morpholinyl.

In other embodiments of Formula II, the phenyl is substituted at thepara position with a group corresponding to a cholesterol molecule.

In certain embodiments of Formula I and Formula II, R³, R⁴, R⁵, R⁶, R⁷and R⁸ are each, independently, a bond to a pharmaceutical agent.

In one aspect, provided herein is a photochromic molecular switchcomprising at least one compound of Formula I or a salt thereof. Inanother aspect, provided herein is a photochromic molecular switchcomprising at least one compound of Formula II or a salt thereof.

In certain embodiments, the molecular switch comprising the salt ofFormula I or the salt of Formula II is reacted with a pharmaceuticallyacceptable salt to form a photopharmaceutical compound. In certainembodiments, the pharmaceutically acceptable salt is a salt of a smallmolecule pharmaceutical.

In one embodiment, the molecular switch comprising the compound ofFormula I or the compound of Formula II or a photopharmaceuticalcompound thereof is stable in water or biological fluid. In anotherembodiment, the molecular switch comprising the compound of Formula I orthe compound of Formula II or a photopharmaceutical compound thereofdoes not substantially hydrolyze in water or biological fluid.

Certain embodiments of Formula I and Formula II are shown in Table A andalso are considered to be “compounds of the invention”.

TABLE A Compound No. Structure NMR and/or MS 1

¹H NMR (500 MHz, CD₂Cl₂) δ 8.42 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 7.5Hz, 1H), 7.91 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.51 (m, 2H), 7.40 (m,2H), 7.20 (m, 2H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 145.39, 144.61,134.66, 134.29, 129.90, 129.84, 129.15, 128.95, 128.65, 127.21, 126.54,126.03, 121.27, 119.63, 114.13 ppm; ¹⁹F NMR (282 MHz, CDCl₃) δ −150.66(q, J = 28.3 Hz, 2F) ppm; GC-MS: calcd for C₁₇H₁₁BF₂N₄, 320.1; m/z (rel.inten.) 320 (15%, M⁺), 140 (29%), 113 (11%), 91 (25%), 77 (100%), 51(35%). 2

¹H NMR (500 MHz, CD₂Cl₂) δ 8.21 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 10.0Hz, 2H), 7.76 (t, J = 5.0 Hz, 1H), 7.72 (d, J = 10.0 Hz, 2H), 7.49 (t, J= 7.5 Hz, 1H), 7.34 (d, J = 10.0 Hz, 1H), 7.03 (d, J = 5.0 Hz, 2H), 3.91(s, 3H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 161.30, 152.71, 144.76, 143.49,139.17, 133.72, 129.60, 125.71, 125.04, 123.28, 118.34, 114.59, 114.20,113.78, 112.91, 55.88 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ −145.95 (q, J =19.7 Hz, 2F) ppm; GC-MS: calcd for C₁₈H₁₃BF₂N₄O, 350.1; m/z (rel.inten.) 350 (23%, M⁺), 144 (10%), 140 (28%), 107 (100%), 91 (22%), 51(32%). 3

¹H NMR (500 MHz, CD₂Cl₂) δ 8.36 (d, J = 10.0 Hz, 1H), 8.06 (d, J = 10.0Hz, 1H), 7.88 (m, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 10.0 Hz,1H), 7.21 (d, J = 10.0 Hz, 1H), 6.66 (d, J = 10.0 Hz, 1H), 6.56 (dd, J =5.0 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ162.75, 161.85, 144.56, 143.48, 134.16, 133.67, 129.53, 125.73, 121.97,119.26, 118.38, 114.17, 114.08, 105.14, 104.72, 99.24, 98.03, 56.46,55.87 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) (δ −150.71 (q, J = 25.4 Hz, 2F)ppm; GC-MS: calcd for C₁₉H₁₅BF₂N₄O₂, 380.1; m/z (rel. inten.) 380 (24%,M⁺), 207 (70%), 137 (26%), 128 (30%), 73 (100%). 4

¹H NMR (500 MHz, CD₂Cl₂) δ 7.94 (d, J = 10.0 Hz, 1H), 7.86 (d, J = 10.0Hz, 2H), 7.72 (d, J = 10.0 Hz, 1H), 7.66 (m, 2H), 7.36 (t, J = 10.0 Hz,1H), 7.15 (d, J = 10.0 Hz, 1H), 6.80 (d, J = 10.0 Hz, 2H), 3.17 (s, 6H)ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 152.49, 141.25, 139.42, 132.86, 129.29,128.25, 128.20, 128.15, 124.48. 124.36, 117.66, 117.64, 114.48, 114.01,112.11, 40.30 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ −150.45 (q, J = 32.0 Hz,2F) ppm; GC-MS: calcd for C₁₉H₁₆BF₂N₅, 363.1; m/z (rel. inten.) 363(20%, M⁺), 281 (4%), 207 (11%), 134 (100%), 120 (49%), 65 (17%). 5

¹H NMR (500 MHz, CD₂Cl₂) δ 7.96 (d, J = 10.0 Hz, 1H), 7.82 (d, J = 7.5Hz, 2H), 7.73 (d, J = 10.0 Hz, 1H), 7.67 (m, 2H), 7.37 (t, J = 10.0 Hz,1H), 7.17 (d, J = 10.0 Hz, 1H), 6.95 (d, J = 10.0 Hz, 2H), 3.51 (t, J =5.0 Hz, 4H), 1.72 (s, 6H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 152.69,141.44, 138.81, 132.94, 129.32, 128.12, 128.04, 124.60, 124.43. 117.72,117.31, 116.41, 114.47, 113.93, 113.74, 48.59, 25.78, 24.54 ppm; ¹⁹F NMR(282 MHz, CD₂Cl₂) δ −150.11 (q, J = 18.8 Hz, 2F) ppm; GC-MS: calcd forC₂₂H₂₀BF₂N₅, 403.2; m/z (rel. inten.) 403 (14%, M⁺), 355 (10%), 281(35%), 253 (12%), 207 (87%), 135 (31%), 73 (100%). 6

¹H NMR (500 MHz, CD₂Cl₂) δ 8.02 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 5.0Hz, 2H), 7.70 (m, 3H), 7.40 (t, J = 10.0 Hz, 1H), 7.21 (d, J = 10.0 Hz,1H), 6.97 (d, J = 7.5 Hz, 2H), 3.48 (t, J = 5.0 Hz, 4H), 2.55 (t, J =5.0 Hz, 4H), 2.33 (s, 3H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 152.46,152.23, 141.96, 139.70, 139.35, 133.13, 129.39, 127.49, 127.39, 124.89,124.58, 117.87, 114.40, 113.97, 113.70, 54.85, 47.22, 46.04 ppm; ¹⁹F NMR(282 MHz, CD₂Cl₂) δ −149.31 (q, J = 18.8 Hz, 2F) ppm; GC-MS: calcd forC₂₂H₂₁BF₂N₆, 418.2; m/z (rel. inten.) 418 (20%, M⁺), 355 (12%), 281(30%), 253 (13%), 207 (84%), 77 (100%). 7

¹H NMR (500 MHz, CD₂Cl₂) δ 8.06 (d, J = 5.0 Hz, 1H), 7.81 (d, J = 7.5Hz, 2H), 7.73 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 10.0 Hz,1H), 6.97 (d, J = 10.0 Hz, 2H), 3.86 (t, J = 5.0 Hz, 4H), 3.41 (t, J=5.0 Hz, 4H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ 152.44, 142.31, 140.35,139.30, 133.32, 129.52, 129.39, 127.09, 126.92. 125.09, 124.69, 117.97,114.36, 114.07, 113.52, 66.65, 47.51 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ−148.73 (q, J = 18.8 Hz, 2F) ppm; GC-MS: calcd for C₂₁H₁₈BF₂N₅O, 405.2;m/z (rel. inten.) 405 (26%, M⁺), 355 (10%), 281 (32%), 253 (11%), 207(83%), 135 (37%), 73 (100%). 8

¹H NMR (500 MHz CD₂Cl₂) δ: 7.81, 7.76, 7.62, 7.55, 7.47, 7.24, 7.03,6.68, 4.33, 3.56, 1.75, 1.47 9

 

¹H NMR (500 MHz, CD₂Cl₂) δ = 8.41 (d, J = 8.9 Hz, 1H), 8.13 (dd, J =6.8, 1.9 Hz, 2H), 7.91 (d, J = 7.9 Hz, 1H), 7.84 (m, 2H), 7.59 (t, J = 8Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.9 Hz, 1H), 5.37 (s,1H), 4.86 (m, 1H), 2.50 (m, 1h), and 2.11-0.062 (cholesterol skeleton).¹³C NMR (126 MHz, CD₂Cl₂) δ = 165.22, 152.68, 144.96, 140.02, 139.11,134.41, 131.12, 130.25, 130.22, 129.77, 128.95, 126.77, 125.73, 122.88,122.40, 118.87, 114.22, 75.00, 71.89, 65.69, 56.97, 56.39, 54.08, 53.86,53.65, 53.43, 53.21, 50.35, 42.52, 40.01, 39.71, 38.40, 37.26, 36.87,36.40, 36.04, 32.17, 32.11, 30.78, 28.42, 28.24, 28.07, 27.96, 24.47,24.02, 22.77, 22.52, 21.27, 19.40, 19.37, 19.10, 18.72, 13.71, 11.84ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ = −150.66 (m, 2F); GC- MS: calcd. forC₄₅H₅₅BF₂N₄O₂ 732.33; m/z (rel. inten.) 732.2 (7.5%, M+).

Photoisomerizable Group

A photoisomerizable group is one that changes from a first isomeric formto a second isomeric form upon exposure to electromagnetic radiation ofdifferent wavelengths, or upon a change in exposure from dark to light,or from light to dark. For example, in some embodiments, thephotoisomerizable group is in a first isomeric form of a compound ofFormula I or a first isomeric form of a compound of Formula II whenexposed to electromagnetic radiation of a first wavelength, and is in asecond isomeric form of a compound of Formula I or a second isomericform of a compound of Formula II when exposed to electromagneticradiation of a second wavelength.

The first wavelength and the second wavelength can differ from oneanother by from about 1 nm to about 600 nm or more, for example, fromabout 1 nm to about 10 nm, from about 10 nm to about 20 nm, from about20 nm to about 50 nm, from about 50 nm to about 75 nm, from about 75 nmto about 100 nm, from about 100 nm to about 125 nm, from about 125 nm toabout 150 nm, or from about 150 nm to about 200 nm, from about 200 nm toabout 500 nm, from about 500 nm to about 600 nm, or more than 600 nm.

In other embodiments, the compound of Formula I or the compound ofFormula II is in a first isomeric form when exposed to light of awavelength λ₁, and is in a second isomeric form in the absence of light(e.g., in the absence of light, the compound undergoes spontaneousrelaxation into the second isomeric form). In these embodiments, thefirst isomeric form of the compound of Formula I or the first isomericform of a compound of Formula II is induced by exposure to light ofwavelength λ₁, and the second isomeric form is induced by not exposingthe compound to light (e.g., keeping the compound in darkness). In otherembodiments, the compound of Formula I or the compound of Formula II isin a first isomeric form in the absence of light (e.g., when thecompound is in the dark; and the compound is in a second isomeric formwhen exposed to light of a wavelength λ₁). In other embodiments, thecompound of Formula I or the compound of Formula II is in a firstisomeric form when exposed to light of a first wavelength λ₁, and thenin a second isomeric form when exposed to light of a second wavelengthλ₂.

For example, in some embodiments provided herein, the compound ofFormula I or the compound of Formula II is in a trans configuration inthe absence of light, or when exposed to light of a first wavelength;and the photoisomerizable group is in a cis configuration when exposedto light of a second wavelength that is different from the firstwavelength.

In some embodiments, the wavelength of light that effects a change inthe compound of Formula I or in the compound of Formula II from a firstisomeric form to a second isomeric form ranges from 400 nanometers to1000 nanometers.

In other embodiments, the wavelength of light that effects a change inthe compound of Formula I or in the compound of Formula II from a firstisomeric form to a second isomeric form ranges from 450 nanometers to850 nanometers.

In other embodiments, the wavelength of light that effects a change inthe compound of Formula I or in the compound of Formula II from a firstisomeric form to a second isomeric form ranges from 710 nanometers to760 nanometers.

The difference between the first wavelength and the second wavelengthcan range from about 1 nm to about 600 nm or more, as described above.Of course, where the synthetic light regulator is switched from light todarkness, the difference in wavelength is from the wavelength λ₂ toessentially zero.

Methods of Using Molecular Switches

The select application of electromagnetic radiation to the compounds ofFormula I or the compounds of Formula II or photopharmaceuticalcompounds comprising a Formula I or Formula II moiety can be used totransform a compound from a trans azo isomeric form to a cis azoisomeric form or vice versa. In this way, the compounds can be used as amolecular switch, with the electromagnetic radiation serving as aswitching means.

In some embodiments, the compounds of Formula I and Formula II orphotopharmaceutical compounds thereof respond to electromagneticradiation that is generated by an infrared light source and/or a visiblelight source. Therefore, in some of these embodiments, the compounds ofFormula I or the compounds of Formula II respond to a first wavelengthλ₁ ranging from 400 nanometers to 1 millimeter to convert the trans azoisomer to the cis azo isomer; and a second wavelength λ₂ ranging from400 nanometers to 1 millimeter causes the cis azo isomer to convert backto the trans azo isomer.

For example, in certain embodiments, the compounds of Formula I or thecompounds of Formula II or photopharmaceutical compounds thereof respondto a first wavelength λ₁ ranging from 700 nanometers to 1000 nanometersto convert the trans azo isomer to the cis azo isomer; and to a secondwavelength λ₂ ranging from 700 nanometers to 1000 nanometers.Additionally, in certain other embodiments, the compounds of Formula Ior the compounds of Formula II or photopharmaceutical compounds thereofrespond to a first wavelength λ₁ ranging from 450 nanometers to 850nanometers to convert the trans azo isomer to the cis azo isomer; and asecond wavelength λ₂ ranging from 450 nanometers to 850 nanometerscauses the cis azo isomer to convert back to the trans azo isomer.

In some other embodiments, the compounds of Formula I or the compoundsof Formula II or photopharmaceutical compounds thereof respond toelectromagnetic radiation that is generated by a visible light source.Therefore, in some of these embodiments, the compounds of Formula I orthe compounds of Formula II or photopharmaceutical compounds thereofrespond to a first wavelength λ₁ ranging from 570 to 750 nanometers toconvert the trans azo isomer to the cis azo isomer; and a secondwavelength λ₂ ranging from 450 to 495 nanometers causes the cis azoisomer to convert back to the trans azo isomer.

The skilled artisan will appreciate that the photochromic materialsdescribed herein need not be limited to those responsive to theexemplary wavelength ranges described herein.

DEFINITIONS

In this disclosure, “comprises,” “comprising,” “containing,” and“having” and the like can have the meaning ascribed to them in U.S.patent law and can mean “includes,” “including,” and the like;“consisting essentially of” or “consists essentially” likewise has themeaning ascribed in U.S. patent law and the term is open-ended, allowingfor the presence of more than that which is recited so long as basic ornovel characteristics of that which is recited is not changed by thepresence of more than that which is recited, but excludes prior artembodiments.

Unless otherwise specified, “a” or “an” means “one or more”.

The term “electromagnetic radiation” as used herein, refers to a form ofenergy exhibiting wave like behavior and having both electric andmagnetic field components, which oscillate in phase perpendicular toeach other as well as perpendicular to the direction of energypropagation. Electromagnetic radiation is classified according to thefrequency of its wave. In order of increasing frequency (f) anddecreasing wavelength (λ), electromagnetic radiation includes: radiowaves (3 Hz≦f≦300 MHz; 1 m≦λ≦100,000 Km), microwaves (300 MHz≦f≦300 GHz;1 mm≦λ≦1 m), infrared radiation (300 GHz≦f≦400 THz; 750 nm≦λ≦1 m),visible light (400 THz≦f≦770 THz; 400 nm≦λ≦1 m), ultraviolet radiation(750 THz≦f≦30 PHz; 10 nm≦λ≦400 nm), X-rays (300 PHz≦f≦30 EHz; 0.01nm≦λ≦10 nm), and gamma rays (f≧15 EHz; λ≦0.02 nm). Hence, the term“electromagnetic radiation”, as used herein, denotes photons,particularly in the visible range and/or in the infrared region.

The term “photochromism”, as used herein, indicates a photoinducedchange in color. Herein, the interconversion usually occurs between twocolored states. A photochromic transformation is always accompanied byprofound absorbance changes in the visible region. In fact, visibleabsorption spectroscopy is the most convenient analytical method tostudy these processes.

The term “photostationary state”, as used herein, indicates a statewhere no further changes in the UV/Vis spectra are observed. Forexample, application of additional electromagnetic energy to a sample ormolecule in a photostationary state does not produce a change inabsorption or emission spectra.

As used herein, the term “molecular switch” refers to a molecule thatgenerates a change in state in response to a signal. In one aspect, amolecular switch is capable of switching from at least one state to atleast one other state in response to the signal.

As used herein, the expression “a group corresponding to” an indicatedspecies expressly includes a radical (including a monovalent, divalentand trivalent radical), for example an aromatic radical or heterocyclicaromatic radical, of the species or group of species provided in acovalently bonded configuration.

As used herein, the term “group” may refer to a functional group of achemical compound. Groups of the present compounds refer to an atom or acollection of atoms that are a part of the compound. Groups of thepresent invention may be attached to other atoms of the compound via oneor more covalent bonds. Groups may also be characterized with respect totheir valence state. The present invention includes groups characterizedas monovalent, divalent, trivalent, etc.

As used herein, the term “substituted” refers to a compound wherein ahydrogen is replaced by another functional group.

As used herein, the term “a small molecule pharmaceutical” refers to acompound, typically an organic compound, with a molecular weight of 900Daltons or less, or 500 Daltons or less, where the compound has atherapeutic functionality or a diagnostic functionality. In someembodiments, a small molecule pharmaceutical is a compound that is,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and that is commensuratewith a reasonable benefit/risk ratio.

As used herein, the term “photopharmaceutical compound” refers to amolecule comprising a molecular switch moiety and a pharmaceuticalcompound moiety, where the moieties may be covalently, ionically orelectrostatically bonded or attracted. In some embodiments, aphotopharmaceutical compound is synthesized by reacting a salt of amolecular switch with a pharmaceutically acceptable salt. Salts ofmolecular switches are compounds wherein the parent compound is modifiedby converting an existing acid or base moiety to its salt form. Examplesof salts include, but are not limited to, mineral or organic acid saltsof basic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The salts can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two.

The term “pharmaceutically acceptable salt” refers to those salts ofpharmaceutical compounds which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.Additionally, “pharmaceutically acceptable salts” refers to compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

As used herein, the term “tissue target” or “target of a tissue” refersto biomolecules or fragments thereof including, but not limited to,hormones, amino acids, peptides, peptidomimetics, proteins, nucleosides,nucleotides, nucleic acids, enzymes, carbohydrates, glycomimetics,lipids, albumins, mono- and polyclonal antibodies, receptors, inclusioncompounds such as cyclodextrins, and receptor binding molecules.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, 1 to 6 carbons, 1 to 4 carbons, or 1 to 3carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like. Furthermore, the expression“C_(x)-C_(y)-alkyl”, wherein x is 1-5 and y is 2-10 indicates aparticular alkyl group (straight- or branched-chain) of a particularrange of carbons. For example, the expression C₁-C₄-alkyl includes, butis not limited to, methyl, ethyl, propyl, butyl, isopropyl, tert-butyland isobutyl.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatedmonocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbonatoms, preferably 3-9, or 3-7 carbon atoms. Exemplary monocyclichydrocarbon groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl andthe like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of the stated number of carbon atomsand from one to five heteroatoms, more preferably from one to threeheteroatoms, selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroalkyl groupis attached to the remainder of the molecule through a carbon atom or aheteroatom.

The term “aryl” includes aromatic monocyclic or multicyclic (e.g.,tricyclic, bicyclic), hydrocarbon ring systems consisting only ofhydrogen and carbon and containing from six to nineteen carbon atoms, orsix to ten carbon atoms, where the ring systems may be partiallysaturated. Aryl groups include, but are not limited to, groups such asphenyl, tolyl, xylyl, anthryl, naphthyl and phenanthryl. Aryl groups canalso be fused or bridged with alicyclic or heterocyclic rings which arenot aromatic so as to form a polycycle (e.g., tetralin).

The term “heteroaryl,” as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocycyl” refers to five-member toten-member, fully saturated or partially unsaturated nonaromaticheterocylic groups containing at least one heteroatom such as O, S or N.The most frequent examples are piperidinyl, morpholinyl, piperazinyl,pyrrolidinyl or pirazinyl. Attachment of a heterocycyl substituent canoccur via a carbon atom or via a heteroatom.

Moreover, the alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl,heteroaryl, and heterocycle groups described above can be“unsubstituted” or “substituted.”

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen on one or more atoms, e.g. C, O or N,of a molecule. Such substituents can independently include, for example,one or more of the following: straight or branched alkyl (preferablyC₁-C₅), cycloalkyl (preferably C₃-C₈), alkoxy (preferably C₁-C₆),thioalkyl (preferably C₁-C₆), alkenyl (preferably C₂-C₆), alkynyl(preferably C₂-C₆), heterocyclic, carbocyclic, aryl (e.g., phenyl),aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g.,phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl,alkylcarbonyl and arylcarbonyl or other such acyl group,heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂),(CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl, —Br, or —I),(CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃(substituted orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₈ cycloalkyl),(CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chainof any naturally occurring amino acid; wherein R′ and R″ are eachindependently hydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, oraryl group.

As is customary and well known in the art, hydrogen atoms are not alwaysexplicitly shown on chemical structures, for example, hydrogen atomsbonded to the carbon atoms of aromatic, heteroaromatic, and alicyclicrings are not always explicitly shown.

The description of the disclosure herein should be construed incongruity with the laws and principals of chemical bonding. For example,it may be necessary to remove a hydrogen atom in order accommodate asubstituent at any given location. Furthermore, it is to be understoodthat definitions of the variables (i.e., “R groups”), as well as thebond locations of the generic formula of the invention (i.e., Formula Ior Formula II), will be consistent with the laws of chemical bondingknown in the art. It is also to be understood that all of the compoundsof the invention described above will further include bonds betweenadjacent atoms and/or hydrogens as required to satisfy the valence ofeach atom. That is, bonds and/or hydrogen atoms are added to provide thefollowing number of total bonds to each of the following types of atoms:carbon: four bonds; nitrogen: three bonds; oxygen: two bonds; andsulfur: two-six bonds.

The compounds of this invention may include asymmetric carbon atoms. Itis to be understood accordingly that the isomers arising from suchasymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers,diastereomers, or racemates) are included within the scope of thisinvention. Such isomers can be obtained in substantially pure form byclassical separation techniques and by stereochemically controlledsynthesis. Furthermore, the structures and other compounds and moietiesdiscussed in this application also include all tautomers thereof.Compounds described herein may be obtained through art recognizedsynthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

EXEMPLIFICATION

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of synthetic and physical organic chemistry as well ascomputational chemistry, which are within the skill of the art.

Example 1 Synthesis of Compound 1 1.1 Synthesis of Hydrozone 1c

1.7 mL of HBF₄ (48%) was added dropwise to a mixture of aniline (0.31mL, 3.4 mmol) in 1 mL water. After stirring in an ice-bath for 40 min, aprecooled solution of NaNO₂ (1 equiv, 0.235 g, 3.4 mmol) was then addeddropwise over a period of 15 min. The white diazonium salt was collectedby filtration after 90 min and added to a suspension of2-quinolylacetonitrile (0.8 equiv, 0.456 g, 2.7 mmol) and sodium acetate(3.2 equiv, 0.890 g, 10.8 mmol) in a cooled and well stirred 30 mLethanol/water (2:1) mixture. The resulting reaction mixture was left tostir overnight at RT. The precipitated compound was then collected byfiltration and dried over air. The crude product was purified by silicagel column chromatography (hexane/ethyl acetate 15:1) to give hydrazone1c as a bright yellow powder (0.550 g, 75%). Mp: 159.8-160.4° C.; ¹H NMR(500 MHz, CDCl₃) δ 16.10 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.05 (d, J=8.5Hz, 1H), 7.86 (m, 2H), 7.81 (t, J=8.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H),7.44 (m, 4H), 7.15 (t, J=9.5 Hz, 1H) ppm; ¹³C NMR (126 MHz, CDCl₃) δ152.31, 145.82, 142.47, 138.00, 131.05, 129.94, 129.81, 128.32, 128.10,127.88, 127.05, 124.70, 119.81, 118.09, 115.50 ppm; GC-MS: calcd forC₁₇H₁₂N₄, 272.1; m/z (rel. inten.) 272 (56%, M⁺), 167 (21%), 140 (34%),105 (15%), 77 (100%), 51 (15%).

1.2 Synthesis of Compound 1

N,N-Diisopropylethylamine (DIPEA, 7 equiv, 0.22 mL, 1.3 mmol) was addedto a solution of hydrazone 1c (0.050 g, 0.18 mmol) in dry methylenechloride at room temperature. After 2 hours, boron trifluoride diethylether complex (10 equiv, 0.23 mL, 1.8 mmol) was added dropwise. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was quenched with water and extracted by methylene chloride. Theorganic layer was washed two times with 10 mL water, 10 mL saturatedsodium bicarbonate solution and dried over magnesium sulfate. Aftersolvent concentration, the crude product was subjected to silica gelcolumn chromatography (methylene chloride/hexane 2:1) to give compound 1as a dark red solid (40 mg, 68%). The compound starts to decompose at177.5° C. before reaching its mp; (¹H NMR 500 MHz, CD₂Cl₂) δ 8.42 (d,J=9.0 Hz, 1H), 8.09 (d, J=7.5 Hz, 1H), 7.91 (m, 2H), 7.63 (t, J=8.0 Hz,1H), 7.51 (m, 2H), 7.40 (m, 2H), 7.20 (m, 2H) ppm; ¹³C NMR (126 MHz,CD₂Cl₂) δ 145.39, 144.61, 134.66, 134.29, 129.90, 129.84, 129.15,128.95, 128.65, 127.21, 126.54, 126.03, 121.27, 119.63, 114.13 ppm; ¹⁹FNMR (282 MHz, CDCl₃) δ −150.66 (q, J=28.3 Hz, 2F) ppm; GC-MS: calcd forC₁₇H₁₁BF₂N₄, 320.1; m/z (rel. inten.) 320 (15%, M⁺), 140 (29%), 113(11%), 91 (25%), 77 (100%), 51 (35%).

The compound (1d) was formed as the minor product during the samereaction of compound 1. After purification by silica gel columnchromatography (hexane/ethyl acetate 5:1), 1d was collected as a brightyellow solid with 10% yield. When the reaction was carried out at 60°C., 1 was obtained as the major product (40% yield). mp 229.2-229.6° C.;¹H NMR (500 MHz, CDCl3) δ 8.87 (d, J=5.0 Hz, 1H), 8.55 (d, J=4.5 Hz,1H), 7.93 (m, 5H), 7.75 (t, J=7.5 Hz, 1H), 7.46 (m, 2H), 7.32 (t, J=7.3Hz, 1H) ppm; ¹³C NMR (126 MHz, CDCl3) δ 144.04, 142.65, 133.96, 129.27,128.87, 127.94, 127.36, 124.05, 123.99, 123.92, 121.09, 121.07, 127.05,117.78, 116.17 ppm; ¹⁹F NMR (282 MHz, CDCl3) δ −124.17 (q, J=28.3 Hz,2F) ppm; GC-MS: calcd for C₁₇H₁₁BF₂N₄, 320.1; m/z (rel. inten.) 320 (4%,M⁺), 154 (2%), 128 (5%), 113 (9%), 101 (8%), 91 (17%), 77 (100%).

Compounds of Formula II can be prepared in accordance with the outlinedsynthesis of Compound I, but starting from aryl-substituted analogues ofaniline 1a (e.g., Compound 2 can be prepared starting fromp-methoxyaniline; Compound 4 can be prepared starting fromp-aminodimethylamine). Subsequently, the substituted aniline can bereduced to a tetrafluoroborate diazonium salt analogous to 1b. Furtherreaction of 1b-analogues afford aryl-substituted analogues of hydrozone1c, which can be used to prepare BF₂-coordinated compounds of FormulaII, as outlined in Example 1.2.

Example 2 Photoisomerism of Compound 1

The photoisomerization of Compound 1 was studied extensively by UV/vis(FIG. 1) spectroscopy. When stored in the dark, Compound 1 adopts itsthermodynamically stable trans form that has an absorption maximum(λ_(max)) at 530 nm (ε=8026 M⁻¹ cm⁻¹). Upon irradiation at 570 nm, thecis form (λ_(max)=480 nm; ε=7792 M⁻¹ cm⁻¹) becomes dominant, accompaniedby a sharp color change of the solution from bright purple to lightorange. The process is also accompanied by changes in the intensity ofbands at higher energies (λ_(max)=340 and 264 nm). Irradiation at 450 nmdrives the system back to its trans form. The isosbestic points(λ_(max)=499, 399, 330, and 257 nm) in the UV/vis spectra demonstratethat only two species are exchanging during the isomerization process(FIG. 1b ). The trans/cis isomerization can be activated solely by theuse of visible light and there is no need for UV light. Furthermore, asshown in FIG. 1c , the system shows very good reversibility as nodegradation of Compound 1 was observed during the entirephotoisomerization studies that lasted for more than a month.

Example 3 The Calculated (B3LPY/6-311++G**)

To understand the effect of Lewis acid coordination on the photophysicalproperties of azo compounds, computational modeling of the trans and cisisomers of Compound 1 was conducted. Structures were optimized bydensity functional theory (DFT) using the B3LYP hybrid functional andthe 6-311++G** basis set, as implemented in Jaguar; this combination ofmethod and basis set is appropriate for such systems. The optimizedstructure of trans-Compound 1 matches well with its crystal structure(FIGS. 4 and 5). Calculations of the UV/Vis spectra of the optimizedstructures were carried out in ADF using time-dependent DFT (TDDFT)using the B3LYP functional and a triple-ζ basis with two addedpolarization functions (TZ2P). These calculations were also successfulin predicting the UV/vis spectra of the cis and trans isomers ofCompound 1 (FIGS. 8 and 9), and show that the absorption bands in thevisible range (FIG. 3, Table C and FIGS. 14-18S37-S41) stem fromπ-nonbonding to π*-antibonding transitions (HOMO→LUMO).

The calculations predict correctly the separation between the cis(λ_(max)=482 nm) and trans bands (λ_(max)=510 nm). Another set ofπ_(nb)-π* transitions (HOMO to LUMO+1) is also predicted at a higherenergy level (λ_(max)=376 and 353 nm for trans and cis, respectively)where a smaller band is clearly visible in the UV/vis spectrum (FIG. 2a), whereas the n-π* transition is, as predicted, at an even shorterwavelength (λ_(max)=338 nm for trans).

Relative to azobenzenes, binding to BF₂ drastically lowers the energy ofthe n-electrons, while additional conjugation in the N—C—C—N—N skeletonprovides a higher energy π_(nb) molecular orbital which serves as theHOMO (FIGS. 14-18S37-S41). This in turns leads to the strong absorptionband in the visible range that enables the manipulation of Compound 1using only visible light. The BF₂ group is not unique in promoting thiseffect. As a proof of concept, the BF₂ group was replaced with Na⁺ (insilico), which also resulted in red-shifted UV/vis absorption spectra(FIGS. 10 and 11). Intriguingly, the trans and cis isomers have aλ_(max) of 466 and 472 nm, respectively. Moreover, the calculationspredict that replacing the CN group with π-electron donating groups(FIGS. 12 and 13) and/or substituting the phenyl ring with such groups(based on the HOMO in FIGS. 6-7) will lead to a red shift in theabsorption band, opening the door for further manipulations of thephotophysical properties of the azo compound.

NMR Photoisomerization Studies

Deoxygenated CD₂Cl₂ solutions of Compound 1 (8.8 mM) in quartz NMR tubeswere used for all the ¹H NMR measurements. Irradiation of the sampleswas conducted with sufficient stirring. The lamp intensity at 450 nm wasdetermined by chemical actinometry using potassium ferrioxalate andferrozine while the intensity at 570 nm was determined by a Thorlabsoptical power meter. The background thermal cis→trans isomerization wasmeasured using ¹H NMR spectroscopy and no observable trans isomer wasformed during the time period used in the irradiation experiments.

Photoisomerization Quantum Yields

The experimental procedure was adapted from Bandara et al. (J. Org.Chem. 2010, 75, 4817). After measuring the light intensities asmentioned above, the photoisomerization quantum yields were determinedby following the change in isomer ratio after a certain period ofirradiation time.

Kinetic Studies

A 0.2 mM deoxygenated CH₂Cl₂ solution of Compound 1 in a quartz cuvettewas irradiated at 570 nm until its photostationary state was reached (nofurther changes in the UV/Vis spectra were observed). The thermalisomerization process was monitored by measuring the change inabsorption intensity at 480 nm as a function of time (at 1 minintervals). The half-life (t_(1/2)) of the cis→trans isomerization wascalculated to be 12.5 h, which is the average of three measurementsconducted at the same conditions.

X-Ray Crystallography

Data were collected using a Bruker CCD (charge coupled device) baseddiffractometer equipped with an Oxford Cryostream low-temperatureapparatus operating at 173 K. Data were measured using omega and phiscans of 1° per frame for 30 s. The total number of images was based onresults from the program COSMO where redundancy was expected to be 4.0and completeness to 0.83 Å to 100%. Cell parameters were retrieved usingAPEX II software and refined using SAINT on all observed reflections.Data reduction was performed using the SAINT software which corrects forLp. Scaling and absorption corrections were applied using SADABSmulti-scan technique, supplied by George Sheldrick. The structures aresolved by the direct method using the SHELXS-97 and refined by leastsquares method on F², SHELXL-97, which are incorporated in SHELXTL-PC V6.10. The structure of Compound 1 was solved in the space group P2₁/c(#14). The aromatic ring was found to be disordered and was modeled at50% in each position. The structure of Compound 1d was solved in thespace group C2/c (#15). All non-hydrogen atoms were refinedanisotropically. Hydrogens were calculated by geometrical methods andrefined as a riding model. Crystals used for the diffraction studiesshowed no decomposition during data collection.

DFT Calculations Computational Methods

All reported DFT calculations were carried out, without any symmetryconstraints, using the robust hybrid B3LYP functional and the 6-311G**++basis set, as implemented in the Jaguar suite of programs. Vibrationalfrequencies were calculated using analytic second derivatives, and allstructures were confirmed as minima by the absence of imaginaryfrequencies. The allowed transitions in the UV spectra for the B3LYPoptimized structures were carried out using TDDFT (B3LYP/TZ2P), asimplemented in the ADF suite of programs.

Example 4 Near Infrared Light Activated Azo-BF₂ Switches

Light penetration through tissue is primarily regulated by theabsorptions of hemoglobin and water,¹ which limits its “therapeuticwindow” to the 600-1200 nm range. In principle, the more red-shifted thewavelength the deeper the penetration, hence, near infrared (NIR) is farbetter than red light in this aspect.² One way of using this property oflight is to couple it with photochromic³ compounds that are capable ofreversibly modulating biological processes. This is the main objectiveof the fields of photopharmacology⁴ and opto(chemical)genetics.⁵ Azocompounds⁶ are the most commonly used light activated switches⁷ in theseresearch areas because of their efficient trans/cis photoisomerization.However, this process generally relies on UV light, which is notbiocompatible.⁸ Consequently, there has been intense activity in thefield in trying to shift the activation wavelength of these photochromiccompounds to the visible region,⁹ and beyond. The burgeoning activityhas led to the development of a number of visible light activated azocompounds, through appropriate derivatization,¹⁰ or the use of metal toligand charge transfer,¹¹ among other approaches.¹² This activity hasrecently paid off with the seminal work by Woolley et al. describing thein vivo activation of an azo compound using red light (635 nm).^(10c)Despite these recent advances there is still a need to develop moreefficient systems, and push the activation wavelength of the azocompounds beyond the red region, in order to gain access to deepertissues.¹³ In this context Qian et al. have recently showed¹⁴ how NIRactivated upconversion nanoparticles¹⁵ can be used in manipulating azocompounds; however, this was accomplished using the NIR lightindirectly, as the azo switch was still modulated using the UV lightemitting from the excited nanoparticles. Furthermore the incorporationof nanoparticles complicates the system, and leads to low isomerizationefficiencies, reducing the practicality of this approach inphotopharmacology and opto(chemical) genetics.

The inventors discovered¹⁶ that the coordination of BF₂ with an azogroup's nitrogen lone-pair leads to a reversal of the positions of n-π*and π-π* transition energy levels. This property enabled switching ofthe azo-compounds using visible (i.e., blue and green) light. DFTcalculations predicted that increasing the electron-density in thesystem could further red-shift the absorption bands, and henceactivation wavelength of the system. A series of azo-BF₂ complexeshaving electron donating para- and ortho-substituents (Scheme 1) weredesigned.¹⁷

This example reports how such substituents shift the azo-BF₂ absorptionbands to the red and even NIR region, thus enabling direct and efficientisomerization of an azo-compound using NIR light. These systems are alsostable to glutathione reduction, and have relatively long lived halflives in aqueous solutions.

As predicted by DFT calculations the introduction of a methoxy grouppara to the azo linkage (Scheme 2) leads to a bathochromic shift in theπ-π* band of 2 (λ_(max)=594 nm, ε=15,998 M⁻¹ cm⁻¹).

The λ_(x) of the cis photostationary state (PSS; irradiation at 630 nm)of compound 2 is red-shifted by 40 nm (FIG. 19a ), while the trans PSS(irradiation at 490 nm) is red-shifted by 55 nm compared with the parentcomplex 1.¹⁶ The switching process of 2 was accompanied with a strongcolor change between cobalt blue and poppy red. High photoconversionratios (PSS490=92% trans, PSS630=96% cis) and a 93% trans isomer ratiounder dark were determined for 2 using ¹H NMR spectroscopic analysis(FIGS. 27 and 26). There are several spectral features of 2 that set itapart from the parent compound; instead of a sharp band, the π-π* bandof the trans-dominant state exhibits a well resolved vibrational finestructure, with the highest-intensity peak observed at λ_(max)=594 nm.The appearance of the sub-bands can be attributed to the intensifiedvibrational transitions caused by the electron-donatingpara-substituent.¹⁸ In addition, the isomerization process in 2 is moreefficient than 1 based on its quantum yields (λ_(trans→cis)=71% andΦ_(cis→trans)=95%). This efficiency enhancement results from a betterseparation of the cis and trans states' π-π* bands, which leads to lessoverlap of their irradiation windows compared to the parent azocomplex 1. The cis isomer of 2 has a half-life of 10.4 h at 294 K indeoxygenated methylene chloride (FIG. 48), compared to 25 min in regularsolvent (not deoxygenated).^(16, 1)

It was recently shown^(10b) that ortho-tetrafluoroazobenzene has aslightly blue shifted π-π* absorption when compared to its parentazobenzene, and that the substitution of the ortho positions withmethoxy groups^(10a) leads to the separation of the n-π* orbital of thecis and trans isomers and a red-shift of the π-π* band in the latter. Inorder to study the ortho-substitution effect, complex 3 (Scheme 3) wasprepared. The extra ortho-methoxy group in 3 causes a 20 nm blue shiftof its trans absorption band relative to 2 (FIG. 19b ). On the otherhand, its cis isomer's π-π* band is red-shifted by 15 nm. The combinedeffect is the generation of a pronounced overlap between the absorptionbands of the two configurations. This overlap resulted in a drasticdecrease in the efficiency of the switch, including its PSS ratio(PSS490=56% and PSS640=79%) and photoswitching quantum yields(Φ_(cis→trans)=51% and Φ_(trans→cis)=42%). The steric hindrance of theortho-OMe group may destabilize the trans isomer, and prevent the phenylring from lying co-planar with the rest of the molecule. The loss ofplanarity in the trans isomer can be inferred by its blue-shiftedabsorption band, and its destabilization is evident from the lower transisomer ratio (58%) under dark.

The BF₂-Azo complexes (4-7) were synthesized with the intention offurther pushing the activation wavelength of the systems to even lowerenergy levels. The attachment of a para-dimethylamino group shifted theabsorption peak of complex 4 to 680 nm (ε=36,255 M⁻¹ cm⁻¹) with a tailextending out to 760 nm (FIG. 20). This property allowed the trans tocis isomerization process to be activated using NIR light. The UV/Visspectrum of the trans isomer of 4 exhibits better-resolved vibrationalfine structure compared to 2. The half-life of the cis isomer of 4 wasdetermined to be 250 seconds (FIG. 49), and no obvious difference inrate was observed by deoxygenating the methylene chloride solution. Theeffective bond order of N═N bond is strongly influenced by thesubstituents on the phenyl rings (vide infra). Electron-donating groupswould cause an increase in the electron density of the π* (antibonding)orbital and thus a decrease in the effective bond order of the N═N bond,which leads to a lower thermal isomerization barrier.^(6,20) Under dark,complex 4 is almost quantitatively (97%) composed of thethermodynamically more stable trans form. Upon irradiation with 710 nmlight, isomerization to the cis isomer occurs quickly. Because of thefast cis to trans isomerization rate we were unable to record the PSS at710 nm. The lowest estimation of the amount of cis isomer at PSS710 is63% based on ¹H NMR spectroscopy (FIG. 35).²¹

The isomerization and photochromic properties of the piperidinyl (5),methylpiperizinyl (6), and morpholinyl (7) BF₂-azo derivatives werestudied (FIG. 21). As can be seen by their UV/Vis spectra, theseswitches all undergo isomerization upon irradiation with 710 nm light,and maintain a high ratio of trans isomer under dark (98%, 94% and 97%trans ratio, with molar extinction coefficient ε=30,458, 29,536 and28,025 M⁻¹ cm⁻¹, for 5, 6 and 7, respectively). The small variation inthe electronic characteristics of the amino groups greatly impacts theirphotophysical properties, including their absorption bands andhalf-lives. The overlay of the absorption bands of compounds 5-7 (FIG.21d ) reveals that the resolution of their vibrational fine structuredecreases in the order of 5>6>7, which is in accordance to theirpara-substituent's electron-donating ability(piperidinyl>methylpiperizinyl>morpholinyl).²² A similar trend is alsoobserved in their absorption maxima (λ_(max)=681 nm, 661 nm and 652 nmfor 5, 6 and 7, respectively). In addition, the half-life relaxationrate from cis to trans is substantially enhanced in switch 7(t_(1/2)=900 s) as compared to 5 (t_(1/2)=150 s) and 6 (t_(1/2)=400 s),which is again in accordance to their electron donation capability. Sucha dramatic change in the half-life of these switches was also reflectedby their PSS710 values. The highest PSS710 ratio for 5 that could bemeasured was 23% while for 6 and 7 it was 49% and 83%, respectively. Thelatter value is comparable to that obtained for the parent azo-BF₂complex 1.

The stability of the switches in an aqueous environment was tested byconducting multiple switching cycles (10 cycles shown in FIG. 22a ) of 4in an acetonitrile:PBS buffer (1:1) mixed solvent system. Theseexperiments were conducted by irradiating the sample using 710 nm light,followed by thermal relaxation under dark. Although switch 4 is stablefor short periods of time under these conditions, it gradually undergoeshydrolysis (FIG. 50), reverting back to the starting hydrazone²³compound (FIG. 22b ) with a half-life of 2.3 h. The stability of switch4 to reduction by glutathione (GSH) was also tested. The switch wasincubated in 10 mM reduced glutathione in acetonitrile:PBS buffer (1:1)solution. No obvious difference was observed in its degradationhalf-life (t_(1/2)=2.5 h) compared to that measured in theacetonitrile/PBS buffer (FIG. 51). The multiple isosbestic pointsobserved in both cases (λ=286 nm, 413 nm and 537 nm) suggest theexistence of only two species in solution, which in this case are theazo-BF₂ complex and the hydrazone starting material. These results,along with similar stability tests conducted for compounds 5-7 (FIGS.52-57), demonstrate the robustness of this class of NIR switches in highconcentrations of GSH. Moreover, the results indicate that coordinationwith BF₂ might be a viable strategy to preventing glutathione reductionof azo compounds.

By comparing the degradation half-life of the complexes in PBS buffer(4≈5>6>7), it is possible to conclude that the higher electron-donatingability of the para-substituent, the more stable the switch is tohydrolysis. According to the crystallographic analysis (FIG. 23), thestronger the electron-donating capability of the para-substituent thelonger the N(1)=N(2) bond (1.294(1) and 1.298(2) Å in 2 and 4,respectively) and shorter the B(1)-N(3) bond and B(1)-N(2) bond lengthsbecome (1.550(2) and 1.624(2) Å in 2, and 1.542(2) and 1.615(2) Å in 4,respectively). The latter trend (i.e., the strengthening of the BNbonds) may make the compounds less susceptible to hydrolysis.

In conclusion, this example shows how the para-substitution of azo-BF₂compounds with electron donating groups leads to photochromic compoundsthat can be activated with NIR light. Structure property analysis showedthat the hydrolysis process in these systems can be modulated and sloweddown using strong electron donating para-substituents. Moreover, theseswitches are not susceptible to reduction by glutathione, most probablybecause of the coordination with BF₂. These results open the way forusing these BF₂-coordinated azo compounds in photopharmacolgical⁴ andopto(chemo)genetical applications.

REFERENCES

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Supporting Information General Methods

All reagents and starting materials were purchased from commercialvendors and used without further purification. Column chromatography wasperformed on silica gel (Silicycle, 230-400 mesh). The melting pointswere measured on an Electrothermal 9100 instrument in open capillarytubes without thermometer correction. Deuterated solvents were purchasedfrom Cambridge Isotope Laboratories and used as received. ¹H NMR and ¹³CNMR spectra were recorded on a 500 MHz spectrometer, with workingfrequencies of 499.87 MHz for ¹H nuclei and 125.7 MHz for ¹³C nuclei,respectively. ¹⁹F NMR spectra were recorded on a 300 MHz spectrometer,with working frequency of 282.2 MHz for ¹⁹F nuclei. Chemical shifts areexpressed in ppm relative to tetramethylsilane, using the residualsolvent peak as a reference standard. GC-MS spectra were measured on aShimadzu Gas Chromatograph/Mass Spectrometer (GCMS-QP2010Plus). UV-Visspectra were recorded on a Shimadzu UV-Vis spectrophotometer (UV-1800).Irradiation experiments were conducted with sufficient stirring using aNewport mercury lamp (67005-414) equipped with a Jarrell-Ash lightmonochromator. The 710 nm Near IR light source was built withappropriate LED light bulbs (LED710-1au AlGaAs Infrared LEDs purchasedfrom Roithner Lasertechnik GmbH). PBS buffer is an aqueous solutionprepared with 11.9 mM sodium phosphate (pH 7.3-7.4), 137 mM NaCl and 2.7mM KCl.

Synthesis

Hydrazone 2: The compound was synthesized following the proceduredescribed previously.^(S1) 1.7 mL of HBF₄ (48%) was added dropwise to amixture of p-anisidine (0.420 g, 3.4 mmol) in 1 mL water. After stirringin an ice-bath for 30 min, a precooled aqueous solution of NaNO₂ (1equiv, 0.235 g, 3.4 mmol) was added dropwise over a period of 15 min.The pinkish diazonium salt was collected by filtration after 60 min andadded to a suspension of 2-quinolylacetonitrile^(S2) (0.8 equiv, 0.456g, 2.7 mmol) and sodium acetate (3.2 equiv, 0.890 g, 10.8 mmol) in acooled and well stirred 30 mL ethanol/water (2:1) mixture. The resultingreaction mixture was left to stir overnight at RT. The precipitatedcompound was then collected by filtration and dried over air. The crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate 9:1) to give Hydrazone 2 as a dark yellow powder (0.572 g, 70%).mp 162.3-162.6° C.; ¹H NMR (500 MHz, CDCl₃) δ16.18 (s, 1H), 8.29 (d,J=10.0 Hz, 1H), 8.02 (d, J=10.0 Hz, 1H), 7.80 (m, 3H), 7.61 (t, J=7.5Hz, 1H), 7.42 (d, J=5.0 Hz, 2H), 6.97 (d, J=5.0 Hz, 2H) ppm; ¹³C NMR(126 MHz, CDCl₃) δ157.18, 152.55, 145.76, 137.79, 136.26, 130.92,128.15, 128.07, 127.62, 126.89, 119.68, 118.43, 116.77, 115.10, 110.34,55.86 ppm; GC-MS: calcd for C₁₈H₁₄N₄O, 302.1; m/z (rel. inten.) 302(56%, M⁺), 195 (23%), 128 (34%), 107 (16%), 31 (12%). FIG. 24 shows a)¹H NMR and b) ¹³C NMR spectra of Hydrazone 2 (contains a smallpercentage of the Z isomer) in CDCl₃ at 294 K.

2: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 2 was collected as a purple powder (54%yield). mp 179.8-180.4° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ8.21 (d, J=10.0Hz, 1H), 7.81 (d, J=10.0 Hz, 2H), 7.76 (t, J=5.0 Hz, 1H), 7.72 (d,J=10.0 Hz, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.34 (d, J=10.0 Hz, 1H), 7.03(d, J=5.0 Hz, 2H), 3.91 (s, 3H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ161.30,152.71, 144.76, 143.49, 139.17, 133.72, 129.60, 125.71, 125.04, 123.28,118.34, 114.59, 114.20, 113.78, 112.91, 55.88 ppm; ¹⁹F NMR (282 MHz,CD₂Cl₂) δ−145.95 (q, J=19.7 Hz, 2F) ppm; GC-MS: calcd for C₁₈H₁₃BF₂N₄O,350.1; m/z (rel. inten.) 350 (23%, M+), 144 (10%), 140 (28%), 107(100%), 91 (22%), 51 (32%). FIG. 25 shows a) ¹H NMR b) ¹³C NMR and c)¹⁹F NMR spectra of 2-trans (contains a small percentage of the cisisomer) in CD₂Cl₂ at 294 K. FIG. 26 shows a ¹H NMR spectrum of 2 afterbeing stored in the dark. The equilibrated mixture of 2 was determinedto have an isomer ratio of 93:7 (trans:cis). FIG. 27 shows a ¹H NMRspectra of the PSS of 2 at a) 490 nm and b) 630 nm in CD₂Cl₂ at 294 K.The PSS isomer ratios of 92±1% trans at l_(irr)=490 nm, and 96±1% cis atl_(irr)=630 nm are the averages of three experiments.

Hydrazone 3: The compound was synthesized following the procedure usedfor Hydrazone 2. Hydrazone 3 was collected as a dark yellow powder (68%yield). mp 164.2-164.7° C.; ¹H NMR (500 MHz, CDCl₃) δ16.08 (s, 1H), 8.18(d, J=10.0 Hz, 1H), 7.96 (d, J=5.0 Hz, 1H), 7.75 (m, 3H), 7.65 (d,J=10.0 Hz, 1H), 7.55 (t, J=5.0 Hz, 1H), 6.55 (m, 2H) 4.06 (s, 3H), 3.83(s, 3H) ppm; ¹³C NMR (126 MHz, CDCl₃) δ157.66, 152.16, 148.93, 145.86,137.29, 130.68, 128.18, 127.90, 127.34, 126.71, 126.08, 119.39, 118.78,115.24, 110.68, 105.46, 99.17, 56.31, 55.88 ppm; GC-MS: calcd forC₁₉H₁₆N₄O₂ 332.1; m/z (rel. inten.) 332 (66%, M⁺), 137 (21%), 128 (15%),77 (100%), 51 (13%). FIG. 28 shows a) ¹H NMR and b) ¹³C NMR spectra ofHydrazone 3 (contains a small percentage of the Z isomer) in CDCl₃ at294 K.

3: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 3 was collected as a purple powder (48%yield). mp 169.3-169.8° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ8.36 (d, J=10.0Hz, 1H), 8.06 (d, J=10.0 Hz, 1H), 7.88 (m, 2H), 7.60 (t, J=7.5 Hz, 1H),7.41 (d, J=10.0 Hz, 1H), 7.21 (d, J=10.0 Hz, 1H), 6.66 (d, J=10.0 Hz,1H), 6.56 (dd, J=5.0 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H) ppm; ¹³C NMR(126 MHz, CD₂Cl₂) δ162.75, 161.85, 144.56, 143.48, 134.16, 133.67,129.53, 125.73, 121.97, 119.26, 118.38, 114.17, 114.08, 105.14, 104.72,99.24, 98.03, 56.46, 55.87 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ−150.71 (q,J=25.4 Hz, 2F) ppm; GC-MS: calcd for C₁₉H₁₅BF₂N₄O₂, 380.1; m/z (rel.inten.) 380 (24%, M⁺), 207 (70%), 137 (26%), 128 (30%), 73 (100%). FIG.29 shows a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 3-cis (containsa small percentage of the trans isomer) in CD₂Cl₂ at 294 K. FIG. 30shows a ¹H NMR spectrum of 3 after being stored in the dark. Theequilibrated mixture of 3 was determined to have an isomer ratio of58:42 (trans:cis). FIG. 31 shows a ¹H NMR spectra of the PSS of 3 at a)490 nm and b) 640 nm in CD₂Cl₂ at 294 K. The PSS isomer ratios of 56±1%trans at l_(irr)=490 nm, and 79±1% cis at l_(irr)=640 nm are theaverages of three experiments.

Hydrazone 4: The compound was synthesized following the procedure usedfor Hydrazone 2. Hydrazone 4 was collected as a brown powder (64%yield). mp 170.3-170.7° C.; ¹H NMR (500 MHz, CDCl₃) δ16.18 (s, 1H), 8.19(d, J=10.0 Hz, 1H), 7.94 (d, J=10.0 Hz, 1H), 7.75 (m, 3H), 7.55 (t,J=10.0 Hz, 1H), 7.34 (d, J=10.0 Hz, 2H), 6.76 (d, J=5.0 Hz, 2H), 2.98(s, 3H) ppm; ¹³C NMR (126 MHz, CDCl₃) δ152.73, 148.49, 145.71, 137.41,137.38, 132.99, 130.70, 127.93, 127.18, 126.65, 119.47, 118.94, 116.83,113.52, 109.04, 41.09 ppm; GC-MS: calcd for C₁₉H₁₇N₅, 315.2; m/z (rel.inten.) 315 (60%, M⁺), 301 (14%), 134 (100%), 119 (46%), 93 (27%), 65(17%). FIG. 32 shows a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 4(contains a small percentage of the Z isomer) in CDCl₃ at 294 K.

4: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 4 was collected as a green powder (65% yield).mp 193.4-193.8° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ7.94 (d, J=10.0 Hz, 1H),7.86 (d, J=10.0 Hz, 2H), 7.72 (d, J=10.0 Hz, 1H), 7.66 (m, 2H), 7.36 (t,J=10.0 Hz, 1H), 7.15 (d, J=10.0 Hz, 1H), 6.80 (d, J=10.0 Hz, 2H), 3.17(s, 6H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ152.49, 141.25, 139.42, 132.86,129.29, 128.25, 128.20, 128.15, 124.48. 124.36, 117.66, 117.64, 114.48,114.01, 112.11, 40.30 ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ−150.45 (q, J=32.0Hz, 2F) ppm; GC-MS: calcd for C₁₉H₁₆BF₂N₅, 363.1; m/z (rel. inten.) 363(20%, M⁺), 281 (4%), 207 (11%), 134 (100%), 120 (49%), 65 (17%). FIG. 33shows a) ¹H NMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 4-trans in CD₂Cl₂at 294 K. FIG. 34 shows a ¹H NMR spectrum of 4 after being stored in thedark. The equilibrated mixture of 4 was determined to have an isomerratio of 97:3 (trans:cis). FIG. 35 shows a ¹H NMR spectrum recording thelowest estimation of PSS of 4 at 710 nm in CD₂Cl₂ at 294 K. The PSSisomer ratio of 63±1% cis at l_(irr)=710 nm is the average of threeexperiments.

Hydrazone 5: The compound was synthesized following the procedure usedfor Hydrazone 2. Hydrazone 5 was collected as a brown powder (51%yield). mp 168.5-168.9° C.; ¹H NMR (500 MHz, CDCl₃) δ16.16 (s, 1H), 8.23(d, J=10.0 Hz, 1H), 7.98 (d, J=10.0 Hz, 1H), 7.78 (m, 3H), 7.58 (t,J=7.5 Hz, 1H), 7.36 (d, J=5.0 Hz, 2H), 6.99 (d, J=10.0 Hz, 2H), 3.17 (t,J=5.0 Hz, 4H), 1.74 (m, 4H), 1.61 (m, 2H) ppm; ¹³C NMR (126 MHz, CDCl₃)δ152.64, 149.95, 145.75, 137.56, 134.91, 130.80, 128.06, 128.00, 127.41,126.76, 119.59, 118.69, 117.63, 116.52, 109.69, 51.15, 24.45, 22.93 ppm;GC-MS: calcd for C₂₂H₂₁N₅, 355.2; m/z (rel. inten.) 355 (51%, M⁺), 160(20%), 140 (28%), 84 (17%), 77 (100%), 51 (16%). FIG. 36 shows a) ¹H NMRand b) ¹³C NMR spectra of Hydrazone 5 (contains a small percentage ofthe Z isomer) in CDCl₃ at 294 K.

5: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 5 was collected as a green powder (56% yield).mp 187.5-188.0° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ7.96 (d, J=10.0 Hz, 1H),7.82 (d, J=7.5 Hz, 2H), 7.73 (d, J=10.0 Hz, 1H), 7.67 (m, 2H), 7.37 (t,J=10.0 Hz, 1H), 7.17 (d, J=10.0 Hz, 1H), 6.95 (d, J=10.0 Hz, 2H), 3.51(t, J=5.0 Hz, 4H), 1.72 (s, 6H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ152.69,141.44, 138.81, 132.94, 129.32, 128.12, 128.04, 124.60, 124.43. 117.72,117.31, 116.41, 114.47, 113.93, 113.74, 48.59, 25.78, 24.54 ppm; ¹⁹F NMR(282 MHz, CD₂Cl₂) δ−150.11 (q, J=18.8 Hz, 2F) ppm; GC-MS: calcd forC₂₂H₂₀BF₂N₅, 403.2; m/z (rel. inten.) 403 (14%, M⁺), 355 (10%), 281(35%), 253 (12%), 207 (87%), 135 (31%), 73 (100%). FIG. 37 shows a) ¹HNMR b) ¹³C NMR and c) ¹⁹F NMR spectra of 5-trans (contains a smallpercentage of the cis isomer) in CD₂Cl₂ at 294 K. FIG. 38 shows a ¹H NMRspectrum of 5 after being stored in the dark. The equilibrated mixtureof 5 was determined to have an isomer ratio of 98:2 (trans:cis). FIG. 39shows a ¹H NMR spectrum recording the lowest estimation of PSS of 5 at710 nm in CD₂Cl₂ at 294 K. The PSS isomer ratio of 28±1% cis atl_(irr)=710 nm is the average of three experiments.

Hydrazone 6: The compound was synthesized following the procedure usedfor Hydrazone 2. Hydrazone 6 was collected as a brown powder (55%yield). mp 163.5-164.0° C.; ¹H NMR (500 MHz, CDCl₃) δ16.03 (s, 1H), 8.13(d, J=10.0 Hz, 1H), 7.87 (d, J=10.0 Hz, 1H), 7.66 (m, 3H), 7.49 (t,J=5.0 Hz, 1H), 7.26 (d, J=10.0 Hz, 2H), 6.90 (d, J=5.0 Hz, 2H), 3.17 (t,J=5.0 Hz, 4H), 2.55 (t, J=5.0 Hz, 4H), 2.32 (s, 3H) ppm; ¹³C NMR (126MHz, CDCl₃) δ152.21, 147.86, 145.45, 140.06, 137.49, 136.94, 135.74,130.71, 129.75, 127.64, 127.38, 119.34, 117.60, 116.57, 116.32, 54.39,48.51, 45.08 ppm; GC-MS: calcd for C₂₂H₂₂N₆, 370.2; m/z (rel. inten.)370 (63%, M⁺), 175 (22%), 140 (36%), 105 (14%), 77 (100%). FIG. 44 showsa) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 6 (contains a smallpercentage of the Z isomer) in CDCl₃ at 294 K.

6: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 6 was collected as a green powder (42% yield).mp 181.7-182.1° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ8.02 (d, J=10.0 Hz, 1H),7.81 (d, J=5.0 Hz, 2H), 7.70 (m, 3H), 7.40 (t, J=10.0 Hz, 1H), 7.21 (d,J=10.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 2H), 3.48 (t, J=5.0 Hz, 4H), 2.55 (t,J=5.0 Hz, 4H), 2.33 (s, 3H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ152.46,152.23, 141.96, 139.70, 139.35, 133.13, 129.39, 127.49, 127.39, 124.89,124.58, 117.87, 114.40, 113.97, 113.70, 54.85, 47.22, 46.04 ppm; ¹⁹F NMR(282 MHz, CD₂Cl₂) δ−149.31 (q, J=18.8 Hz, 2F) ppm; GC-MS: calcd forC₂₂H₂₁BF₂N₆, 418.2; m/z (rel. inten.) 418 (20%, M⁺), 355 (12%), 281(30%), 253 (13%), 207 (84%), 77 (100%). FIG. 45 shows a) ¹H NMR b) ¹³CNMR and c) ¹⁹F NMR spectra of 6-trans (contains a small percentage ofthe cis isomer) in CD₂Cl₂ at 294 K. FIG. 46 shows a ¹H NMR spectrum of 6after being stored in the dark. The equilibrated mixture of 7 wasdetermined to have an isomer ratio of 97:3 (trans:cis). FIG. 47 shows a¹H NMR spectrum recording the lowest estimation of PSS of 6 at 710 nm inCD₂Cl₂ at 294 K. The PSS isomer ratio of 49±1% cis at l_(irr)=710 nm isthe average of three experiments.

Hydrazone 7: The compound was synthesized following the procedure usedfor Hydrazone 2. Hydrazone 7 was collected as a brown oil (56% yield).¹H NMR (500 MHz, CDCl₃) δ16.08 (s, 1H), 8.20 (d, J=10.0 Hz, 1H), 7.94(d, J=10.0 Hz, 1H), 7.75 (m, 3H), 7.56 (t, J=7.5 Hz, 1H), 7.34 (d,J=10.0 Hz, 2H), 6.95 (d, J=10.0 Hz, 2H), 3.88 (t, J=5.0 Hz, 4H), 3.17(t, J=5.0 Hz, 4H) ppm; ¹³C NMR (126 MHz, CDCl₃) δ152.47, 148.83, 145.67,137.60, 135.63, 130.86, 128.06, 128.00, 127.52, 126.76, 119.54, 118.52,116.91, 116.54, 110.04, 69.09, 49.84 ppm; GC-MS: calcd for C₂₁H₁₉N₄O,357.2; m/z (rel. inten.) 357 (64%, M⁺), 162 (18%), 140 (31%), 105 (18%),77 (100%). FIG. 40 shows a) ¹H NMR and b) ¹³C NMR spectra of Hydrazone 7(contains a small percentage of the Z isomer) in CDCl₃ at 294 K.

7: The compound was synthesized following the procedure describedpreviously.^(S1) Compound 7 was collected as a green powder (45% yield).mp 174.8-175.3° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ8.06 (d, J=5.0 Hz, 1H),7.81 (d, J=7.5 Hz, 2H), 7.73 (m, 3H), 7.42 (t, J=7.5 Hz, 1H), 7.24 (d,J=10.0 Hz, 1H), 6.97 (d, J=10.0 Hz, 2H), 3.86 (t, J=5.0 Hz, 4H), 3.41(t, J=5.0 Hz, 4H) ppm; ¹³C NMR (126 MHz, CD₂Cl₂) δ152.44, 142.31,140.35, 139.30, 133.32, 129.52, 129.39, 127.09, 126.92. 125.09, 124.69,117.97, 114.36, 114.07, 113.52, 66.65, 47.51 ppm; ¹⁹F NMR (282 MHz,CD₂Cl₂) δ−148.73 (q, J=18.8 Hz, 2F) ppm; GC-MS: calcd for C₂₁H₁₈BF₂N₅O,405.2; m/z (rel. inten.) 405 (26%, M⁺), 355 (10%), 281 (32%), 253 (11%),207 (83%), 135 (37%), 73 (100%). FIG. 41 shows a) ¹H NMR b) ¹³C NMR andc) ¹⁹F NMR spectra of 7-trans (contains a small percentage of the cisisomer) in CD₂Cl₂ at 294 K. FIG. 42 shows a ¹H NMR spectrum of 7 afterbeing stored in the dark. The equilibrated mixture of 7 was determinedto have an isomer ratio of 94:6 (trans:cis). FIG. 43 shows a ¹H NMRspectrum recording the lowest estimation of PSS of 7 at 710 nm in CD₂Cl₂at 294 K. The PSS isomer ratio of 82±1% cis at l_(irr)=710 nm is theaverage of three experiments.

8: The compound was synthesized following the procedure describedpreviously.^(S1 1)H NMR (500 MHz CD₂Cl₂) δ: 7.81, 7.76, 7.62, 7.55,7.47, 7.24, 7.03, 6.68, 4.33, 3.56, 1.75, 1.47

9: Compound 9 includes a ester linked cholesterol substituent in thepara position. The compound starts to decompose at 195.5° C. beforereaching its mp; ¹H NMR (500 MHz, CD₂Cl₂) δ=8.41 (d, J=8.9 Hz, 1H), 8.13(dd, J=6.8, 1.9 Hz, 2H), 7.91 (d, J=7.9 Hz, 1H), 7.84 (m, 2H), 7.59 (t,J=8 Hz, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.9 Hz, 1H), 5.37 (s,1H), 4.86 (m, 1H), 2.50 (m, 1h), and 2.11-0.062 (cholesterol skeleton).¹³C NMR (126 MHz, CD₂Cl₂) δ=165.22, 152.68, 144.96, 140.02, 139.11,134.41, 131.12, 130.25, 130.22, 129.77, 128.95, 126.77, 125.73, 122.88,122.40, 118.87, 114.22, 75.00, 71.89, 65.69, 56.97, 56.39, 54.08, 53.86,53.65, 53.43, 53.21, 50.35, 42.52, 40.01, 39.71, 38.40, 37.26, 36.87,36.40, 36.04, 32.17, 32.11, 30.78, 28.42, 28.24, 28.07, 27.96, 24.47,24.02, 22.77, 22.52, 21.27, 19.40, 19.37, 19.10, 18.72, 13.71, 11.84ppm; ¹⁹F NMR (282 MHz, CD₂Cl₂) δ=−150.66 (m, 2F); GC-MS: calcd. forC₄₅H₅₅BF₂N₄O₂ 732.33; m/z (rel. inten.) 732.2 (7.5%, M⁺).

Kinetics Studies

A 0.1 mM deoxygenated CH₂Cl₂ solution of compound 2 in a quartz cuvettewas irradiated at 630 nm until its photostationary state was reached (nofurther changes in the UV-Vis spectra were observed). The thermalisomerization process was monitored by measuring the change inabsorption intensity at 594 nm as a function of time (at 1 minintervals). The half-life (t_(1/2)) of the cis→trans isomerization for 2was calculated to be 10.4 h, which is the average of three measurementsconducted under the same conditions. When the rate was measured in anunaltered solution, the half-life of 2 went down to 25 min. Thehalf-life of 3 was measured as well in deoxygenated CH₂Cl₂, and wasdetermined to be 13.4 h.

Unaltered CD₂Cl₂ solution of compound 4 in a quartz NMR tube wasirradiated at 710 nm until its photostationary state was reached. Thethermal isomerization process was monitored by measuring the change inthe integrations of diagnostic peaks of both cis and trans isomers as afunction of time (at 30 seconds intervals). The half-life (t_(1/2)) ofthe cis→trans isomerization was calculated to be 250 s, which is theaverage of three measurements conducted under the same conditions. Noobvious change was observed in deoxygenated samples of 4. Similarkinetics experiments were carried out for compounds 5-7, and theirhalf-lives are summarized in Table B.

TABLE B The cis→trans thermal relaxation rates for 4-7 in CD₂Cl₂ at 294K. Compound 4 5 6 7 Half-life 250 s 150 s 400 s 900 s

X-Ray Crystallography

Data were collected using a Bruker CCD (charge coupled device) baseddiffractometer equipped with an Oxford Cryostream low-temperatureapparatus operating at 173 K. Data were measured using omega and phiscans of 10 per frame for 30 s. The total number of images was based onresults from the program COSMO^(S3) where redundancy was expected to be4.0 and completeness to 0.83 Å to 100%. Cell parameters were retrievedusing APEX II software^(S4) and refined using SAINT on all observedreflections. Data reduction was performed using the SAINT software^(S5)which corrects for Lp. Scaling and absorption corrections were appliedusing SADABS^(S6) multi-scan technique, supplied by George Sheldrick.The structures are solved by the direct method using the SHELXS-97 andrefined by least squares method on F², SHELXL-97, which are incorporatedin SHELXTL-PC V 6.10.^(S7) The structure of 2 and 4 were solved in thespace group P2₁/c. All non-hydrogen atoms are refined anisotropically.Hydrogens were calculated by geometrical methods and refined as a ridingmodel. Crystals used for the diffraction studies showed no decompositionduring data collection.

Preparation of the Crystal Sample of 2:

Compound 2 (20 mg) was dissolved in 3 mL methylene chloride. Thesolution was stored in the dark and allowed to evaporate over 2 days.Dark yellow plate crystals were collected.

Preparation of the Crystal Sample of 4:

Compound 4 (20 mg) was dissolved in 3 mL methylene chloride. Thesolution was stored in the dark and allowed to evaporate over 2 days.Red block crystals were collected.

TABLE C Crystal Data and Parameters for 2 and 4. 2 4 Empirical formulaC₁₈H₁₃BF₂N₄O C₁₉H₁₆BF₂N₅ Formula weight 350.13 363.18 Temperature 172.99K 173.15 K Wavelength 1.54178 Å 0.71073 Å Crystal system MonoclinicMonoclinic Space group P 2₁/c P 2₁/c Unit cell dimensions a = 16.9594(2)Å a =17.6056(13) Å α = 90° α = 90° b = 12.7408(2) Å b = 13.5354(10) Å β= 94.1250(1)° β = 100.3040(10)° c =7.2440(1) Å c = 7.3372(5) Å γ = 90°.γ = 90°. Volume 1561.20(4) Å³ 1720.2(2) Å³ Z 4 4 Density (calculated)1.490 Mg/m³ 1.402 Mg/m³ Absorption coefficient 0.938 mm⁻¹ 0.101 mm⁻¹F(000) 720 752 Crystal size 0.279 × 0.171 × 0.05 mm³ 0.391 × 0.198 ×0.132 mm³ Theta range for data 8.688 to 136.638° 3.82 to 50.74°collection Index ranges −20 <= h <= 19, −15 <= k <= 15, −21 <= h <= 21,−16 <= k <= 16, −8 <= 1 <= 8 −8 <= 1 <=8 Reflections collected 1159527436 Independent reflections 2863 [R(int) = 0.0249] 3145 [R(int) =0.0433] Goodness-of-fit on F² 1.037 1.050 Final R indices [I > 2σ(I)] R₁=0.0315, ωR₂ = 0.0877 R₁ = 0.0365, ωR₂ = 0.0874 R indices (all data) R₁=0.0372, ωR₂ = 0.0923 R₁ = 0.0538, ωR₂ = 0.0954

REFERENCES

-   (S1) Yang, Y.; Hughes, R. P.; Aprahamian, I. J. Am. Chem. Soc. 2012,    134, 15221-15224.-   (S2) (a) Lipshutz, B. H.; Kim, S.; Mollard, P.; Blomgren, P. A.;    Stevens, K. L. Tetrahedron 1998, 54, 6999-7012. (b) Domasevitch, K.    V.; Gerasimchuk, N. N.; Mokhir, A. Inorg. Chem. 2000, 39, 1227-1237.-   (S3) COSMO V1.61, Software for the CCD Detector Systems for    Determining Data Collection Parameters. Bruker Analytical X-ray    Systems, Madison, Wis. (2009).-   (S4) APEX2 V2010.11-3. Software for the CCD Detector System; Bruker    Analytical X-ray Systems, Madison, Wis. (2010).-   (S4) SAINT V 7.68A Software for the Integration of CCD Detector    System Bruker Analytical X-ray Systems, Madison, Wis. (2010).-   (S5) Blessing, R. H. Acta Cryst. A 1995, 51, 33-38.-   (S6) Sheldrick, G. M. Acta Cryst. A 2008, 64, 112-122.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

What is claimed is:
 1. A compound of the Formula II:

or a salt thereof, wherein N═N—R² can be oriented cis or trans to thetricycle; R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl,OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl); R² is C₆₋₁₉-aryl orC₃₋₁₄-heteroaryl; and R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently,H, C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, NHC(O)(C₁₋₆-alkyl) or a groupcorresponding to a small molecule pharmaceutical; or R³ and R⁴, R⁴ andR⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together, form a fused aryl,fused heteroaryl, fused C₃₋₆-cycloalkyl, or fused heterocycle, whereinthe fused aryl, fused heteroaryl, fused cycloalkyl, or fused heterocyclecan be optionally substituted one or more times with C₁₋₆-alkyl,C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).
 2. The compound of claim 1,wherein R² is unsubstituted C₆₋₁₉-aryl or unsubstitutedC₃₋₁₄-heteroaryl.
 3. The compound of claim 1, wherein R³, R⁴, R⁵, R⁶, R⁷and R⁸ are each, independently, H.
 4. The compound of claim 1, whereinR¹ is CN.
 5. The compound of claim 1, wherein R² is phenyl, wherein thephenyl is substituted with N(C₁₋₆-alkyl)₂, O(C₁₋₆-alkyl), piperazinyl,(N-methyl)piperazinyl, piperidinyl, morpholinyl or a group correspondingto a cholesterol molecule.
 6. The compound of claim 1, wherein R² isphenyl, wherein the phenyl is substituted at the para position withN(CH₃)₂, OCH₃, piperazinyl, (N-methyl)piperazinyl, piperidinyl,morpholinyl or a group corresponding to a cholesterol molecule.
 7. Thecompound of claim 1, wherein N═N—R² is oriented cis to the tricycle. 8.The compound of claim 1, wherein N═N—R² is oriented trans to thetricycle.
 9. The compound of claim 1, wherein R² is unsubstitutedphenyl.
 10. A photochromic molecular switch comprising at least onecompound of the Formula II:

or a salt thereof, wherein N═N—R² can be oriented cis or trans to thetricycle; R¹ is H, CN, CO₂H, CO₂(C₁₋₆-alkyl), C₁₋₆-alkyl, C₆₋₁₉-aryl,OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl); R² is C₆₋₁₉-aryl orC₃₋₁₄-heteroaryl; and R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are each, independently,H, C₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl); or R³ and R⁴, R⁴and R⁵, R⁵ and R⁶ or R⁷ and R⁸ can, when taken together, form a fusedaryl, fused heteroaryl, fused C₃₋₆-cycloalkyl, or fused heterocycle,wherein the fused aryl, fused heteroaryl, fused cycloalkyl, or fusedheterocycle can be optionally substituted one or more times withC₁₋₆-alkyl, C₆₋₁₉-aryl, OH, O(C₁₋₆-alkyl), OC(O)(C₁₋₆-alkyl), NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, or NHC(O)(C₁₋₆-alkyl).
 11. Thephotochromic molecular switch of claim 10, wherein R² is unsubstitutedC₆₋₁₉-aryl or unsubstituted C₃₋₁₄-heteroaryl.
 12. The photochromicmolecular switch of claim 10, wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areeach, independently, H.
 13. The photochromic molecular switch of claim10, wherein R¹ is CN.
 14. The photochromic molecular switch of claim 10,wherein R² is phenyl, wherein the phenyl is substituted withN(C₁₋₆-alkyl)₂, O(C₁₋₆-alkyl), piperazinyl, (N-methyl)piperazinyl,piperidinyl, morpholinyl or a group corresponding to a cholesterolmolecule.
 15. The photochromic molecular switch of claim 10, wherein R²is phenyl, wherein the phenyl can be optionally substituted at the paraposition with N(CH₃)₂, OCH₃, piperazinyl, (N-methyl)piperazinyl,piperidinyl, morpholinyl or a group corresponding to a cholesterolmolecule.
 16. The photochromic molecular switch of claim 10, whereinN═N—R² is oriented cis to the tricycle.
 17. The photochromic molecularswitch of claim 10, wherein N═N—R² is oriented trans to the tricycle.18. The photochromic molecular switch of claim 10, wherein R² isunsubstituted phenyl.
 19. A method of switching a molecular switch,wherein the molecular switch comprises a compound of Formula I or saltthereof wherein the method comprises applying electromagnetic radiationto the molecular switch at a first wavelength effective to cause thetrans→cis isomerization of the compound of Formula I or salt thereof orapplying electromagnetic radiation to the molecular switch at a secondwavelength effective to cause the cis→trans isomerization of thecompound of Formula I or salt thereof or a combination thereof.
 20. Themethod of claim 19, wherein the electromagnetic radiation is generatedby an infrared light source and/or a visible light source.
 21. Themethod of claim 19, wherein the electromagnetic radiation is generatedby a visible light source.
 22. The method of claim 20, wherein the firstwavelength (λ) is between 400 nanometers and 1000 nanometers.
 23. Themethod of claim 20, wherein the second wavelength (λ) is between 400nanometers and 1000 nanometers.
 24. The method of claim 20, wherein thefirst wavelength (λ) is between 450 nanometers and 850 nanometers. 25.The method of claim 20, wherein the second wavelength (λ) is between 450nanometers and 850 nanometers.
 26. The molecular switch of claim 10,wherein the salt of Formula I is reacted with a pharmaceuticallyacceptable salt to form a photopharmaceutical compound.
 27. A method oftreating a patient in need of therapy, comprising: administering atherapeutically effective amount of the photopharmaceutical compound ofclaim 27 to a patient in need thereof; and applying electromagneticradiation to a tissue comprising the photopharmaceutical compound at afirst wavelength effective to cause the trans→cis isomerization orapplying electromagnetic radiation to the photopharmaceutical compoundat a second wavelength effective to cause the cis→trans isomerization ora combination thereof, wherein one isomer has a higher binding affinityfor a target of the tissue than the other isomer.
 28. The method ofclaim 27, wherein the electromagnetic radiation is generated by aninfrared light source and/or a visible light source.
 29. The compound ofclaim 1, wherein the C6-19-aryl or C3-14-heteroaryl is independentlysubstituted one or more times at the para and/or ortho position withC1-6-alkyl, C6-19-aryl, C3-14-heteroalkyl, OH, O(C1-6-alkyl),OC(O)(C1-6-alkyl), NH2, NH(C1-6-alkyl), N(C1-6-alkyl)2, orNHC(O)(C1-6-alkyl).
 30. The photochromic molecular switch of claim 10,wherein the C6-19-aryl or C3-14-heteroaryl is independently substitutedone or more times at the para and/or ortho position with C1-6-alkyl,C6-19-aryl, C3-14-heteroalkyl, OH, O(C1-6-alkyl), OC(O)(C1-6-alkyl),NH2, NH(C1-6-alkyl), N(C1-6-alkyl)2, NHC(O)(C1-6-alkyl) or a groupcorresponding to a small molecule pharmaceutical.